Indole derivatives and process for their preparation

ABSTRACT

Substituted indole derivatives of formula (I) 
                         
wherein the radicals have e.g. the following meaning:
     R 1  is hydrogen, —C 1-6 -alkyl, R 2  is hydrogen, —C 1-6 -alkyl or cycloC 3-12 -alkyl;   R 3  is —OR   R 4  is hydrogen or halogen,   R 5  is hydrogen, —C 1-6 -alkyl   R 6  is hydrogen, —C 1-6 -alkyl   R is hydrogen or —C 1-6 -alkyl;   X is a group —C(O)CH 2 — or —CH═CH—;   R 7  is hydrogen
 
are potent inhibitors of Abeta peptide polymerization and can be used for the treatment of e.g. Alzheimers disease or ocular disorders.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/881,626 filed on Jul. 19, 2013, which is a National Phase of PCTPatent Application No. PCT/EP2011/068820 filed on Oct. 27, 2011, whichclaims the benefit of priority of U.S. Provisional Patent ApplicationNo. 61/407,924 filed on Oct. 29, 2010 and of European Patent ApplicationNo. 10189377.4 filed on Oct. 29, 2010.

The contents of the above applications are all incorporated by referenceas if fully set forth herein in their entirety.

The present invention relates to indole derivatives, which can act asmodulators of the aggregation and/or polymerization of β-amyloidpeptides (Abeta peptides). The invention also is directed to methods forthe preparation of indole derivatives and their use as a medicament forthe treatment and/or prevention of various diseases and disorders. Thecompounds can e. g. be used against neurological diseases and oculardisorders.

The present invention in particular relates to the prevention andtreatment of CNS-related diseases and ocular disorders, in particular ofglaucoma. The compounds can act through blocking the negative effects ofAbeta peptides. The invention also relates to pharmaceuticalcompositions for effecting such prevention and treatment.

FIELD AND BACKGROUND OF THE INVENTION

The treatment of CNS diseases and ocular disorders are worldwideimportant fields of research. Several heterocyclic compounds have shownto interact with neurotransmitters which are released by neurons of thecentral nervous system (CNS). Some compounds have been tested for thetreatment of CNS-disorders such as Alzheimers disease. Scientificstudies have also shown that glaucoma is a leading cause of blindness.One pathologic sign of glaucoma is the progressive degeneration ofretinal ganglion cells and their axons which form the optic nerve. Theclassification of glaucoma also includes the following types:

-   -   Primary angle-closure glaucoma, secondary open-angle glaucoma,        steroid-induced glaucoma, traumatic glaucoma, pigmentary        dispersion syndrome, pseudo-exfoliation syndrome, secondary        angle-closure glaucoma, neovascular glaucoma, uveitis and        glaucoma and other non further specified eye pathologies.

In addition, age-related macular degeneration is a typical conditionwhich has features of glaucoma and leads to a progressive loss ofvision, leading finally to blindness. The treatment of ocular diseasesincludes the treatment of elevation in the intraocular pressure (IOP)over a normal range. Many individuals with clearly have elevated IOP donot develop glaucoma, and many patients with glaucoma do not have anincreased IOP.

Currently available medications/drug compounds for the treatment ofocular diseases, in particular glaucoma, belong to severalpharmacological classes, including β-adrenergic blockers, cholinergicagonists, carbonic anhydrase inhibitors and alpha agonists. All of themoperate under a mechanism whereby the IOP is lowered. These existingmedications are typically administered locally, e.g. as eye drops.Hyperosmotics may also be administered intravenously for emergencytreatment. In addition, laser therapy and surgical approaches areapplied in special cases of ocular diseases.

There is however an unmet medical need for better pharmaceutical drugcompounds and alternative treatment strategies. Particularly forpatients with progressive glaucomatous damage under normalized IOP, adrug therapy focusing on the rescue of degenerating retinal ganglioncells is needed. A particular need is for stable drug compounds whicheasily can be applied to humans and other mammals.

There are different scientific theories regarding the causes for thedegeneration of the retinal ganglion cells including mechanical,vascular and excitotoxic mechanisms. The β-amyloid peptide has beenfound to co-localize with dying retinal ganglion cells [see Yoneda S,“Vitreous fluid levels of beta-amyloid (1-42) and tau in patients withretinal diseases”, Jpn. J. Ophthalmol. 2005, 49(2) p.106-108].Furthermore, animal studies demonstrated that the soluble Aβ₁₋₄₂ peptideoligomers are potent toxins for retinal ganglion cells [see Guo L,“Targeting amyloid-β in glaucoma treatment”, PNAS 2007, 104(33),p.13444-13449]. This study of L. Guo showed that inhibition ofaggregation of Abeta reduces glaucomatous degeneration of retinalganglion cells. The inhibitors used in the animal experiments were knowncompounds, such as the diazo-biphenyl-derivative Congo red and Abetaantibodies. These agents however are pharmacological research toolsonly. Abeta antibodies are known to block Abeta aggregationspecifically, however the usefulness of anti-Abeta antibodies for thetreatment of glaucoma in humans is limited by known side effects.

Some β-Secretase inhibitors can have beneficial effects on Abeta-relatedneurotoxicity, however the observed effects in rat retinal ganglioncells were not significant. In the literature, various types ofsubstituted indole compounds have been disclosed which have interestingpharmaceutical properties. Some known peptidic indole derivatives can beused for pharmaceutical purposes, such as the treatment of diabetes,Alzheimers disease and others [see e.g. WO2005/000193 andWO2009/024346]. Also, neuro-protective pharmaceutical compositions havebeen described [see WO2003/063760 and WO2003/077869]. Several compoundsthat inhibit Abeta polymerization and which are effective in animalmodels are described in the scientific literature, e. g.cyclohexanehexol compounds [see J. Mc Laurin, Nature Medicine 12(7),2006, p. 801-808].

Solutions of the phenolic yellow curry pigment curcumin were found toinhibit Abeta aggregation in vitro [see F. Yang, Journal of BiologicalChemistry 208(7), 2005, p. 5892-5901].

However, the substances described in the prior art, are often notsufficiently active in inhibiting Abeta aggregation and/orpolymerization or they have unwanted side-effects.

In the publication of Y. K. Shue, “Double bond isosteres of the peptidebond: Synthesis and biological activity of cholecystokinin (CCK)C-terminal hexapeptide analogs” (Bioorganics & Medicinal Chemistry 1,No. 3, 1993, 161-179) several indol compounds are described, which canbe used for this synthesis of tetra-peptides.

As one compound, the structure (D1) is shown.

In the publication of B. E. Kornberg “Synthesis of TRP-VAL non-cleavabledipeptide transition state isosteres” (Bioorganics & Medicinal Chemistry3, No. 6, 1993, 1257-1262), a multiple step preparation is described. Inthis article, the following reaction is shown to lead to the structure(D2).

In the publication of Maria Teresa Garcia-Lopez “Synthesis andInhibitory Activities against Aminopeptidase B and Enkephalin-DegradingEnzymes of Ketomethylene Dipeptide Analogues of Arphamenines” (Archivder Pharmazie, 325, No. 1, 1992, 3-8) various dipeptide compounds aredescribed which have inhibitory activities against Aminopeptidase B.

In the publication of Maria Teresa Garcia-Lopez “Synthesis ofketomethylene dipeptides containing basic amino acid analogues atC-terminus” (Tetrahedron, 44, No. 16, 1988, 1531-1538) severalindol-derivatives are described such as the following compound (D4).

In the international patent application WO 1988/03927 various types ofRenin-inhibitory peptides are disclosed, which as one amino acid cancomprise L-tryptophan. In the document WO 2005/060683, several types ofsmall peptides are described which can be useful for the treatment ofAlzheimers disease. Several of the peptides disclosed can comprise atryptophan structure.

SUMMARY OF THE INVENTION

It now has been found that certain indole derivatives which differ instructure from the compounds described in the prior art can interactwith neurotransmitters in the central nervous system. The compounds alsoare potent inhibitors of the Abeta aggregation and/or polymerization.Therefore, these indole derivatives can be therapeutically beneficial inthe treatment of conditions which involve abnormal Abeta polymerizationor in which modulation of Abeta polymerization results in therapeuticbenefit, such as CNS and ocular disorders and diseases.

The invention in particular relates to an indole compound of formula (I)

wherein

-   -   R¹ is hydrogen, —C₁₋₆-alkyl, cycloC₃₋₁₂-alkyl, —C(O)—R or        —C(O)OR;    -   R² is hydrogen, —C₁₋₆-alkyl or cycloC₃₋₁₂-alkyl;    -   R³ is —OR, —NHR or —NR₂;    -   R⁴ is hydrogen, halogen, cyano, trifluoromethyl, —C₁₋₆-alkyl,        —C₆₋₁₀-aryl, heteroaryl, —OR, —NHR, —NRR, —C(O)—R or —C(O)—NHR;    -   R⁵ is hydrogen, —C₁₋₆-alkyl or C₂₋₆-alkenyl; or    -   R⁵ and R⁶ together with the carbon atom carrying them form a        cyclic system with 3 to 6 carbon atoms;    -   R⁶ is hydrogen, —C₁₋₆-alkyl or C₂₋₆-alkenyl;    -   R is hydrogen, —C₁₋₆-alkyl, or —C₆₋₁₀-aryl;    -   X is a group —C(O)CH₂—, —CH(OH)CH₂—, —CH═CH— or —CH₂—NH—C(O)—;    -   R⁷ is hydrogen, methyl, ethyl, propyl or cyclopropyl        or an optical isomer, pharmaceutically acceptable salt, hydrate,        solvate, or polymorph thereof.

The present invention also includes all optical isomers,pharmaceutically acceptable salts, hydrates, solvates and polymorphs ofthe compounds of formula (I). The invention also relates to analogs andderivatives of compounds of formula (I).

The two substituents R⁵ and R⁶ can, together with the carbon atomcarrying them, form a cyclic system with 3 to 6 carbon atoms. Thiscyclic system can also contain one ring element from the group —O—, —S—or —NH—. Typical cyclic systems are e.g. cyclohexane, cyclopentane,cyclobutane, cyclopropane, oxetane and acetidine rings.

The groups R¹, R² and R³ often denote independently of each other,hydrogen or C₁₋₃-alkyl. The term “C₁₋₆-alkyl” represents straight orbranched chain alkyl groups such as methyl, ethyl, n-propyl, 2-propyl,n-butyl and tert-butyl.

The alkyl group may in one embodiment of the invention be optionallysubstituted by one to five substituents selected from halogen, amino orhydroxyl, or the group —CF₃.

The term “C₂₋₆-alkenyl” represents straight or branched chain alkenylgroups.

The term “cycloC₃₋₁₂-alkyl” represents monocyclic or bicyclic, alkylgroups, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Thecycloalkyl groups in one embodiment of the invention may be optionallysubstituted by one to five substituents selected from halogen, amino orhydroxyl.

The term “C₆₋₁₀-aryl” represents phenyl or naphthyl, wherein the phenylor naphthyl group may in one embodiment of the invention be optionallysubstituted by one to five substituents selected from halogen, amino orhydroxyl.

The term “heteroaryl” represents an aromatic 5-6 membered ringcontaining from one to four heteroatoms selected from oxygen, sulfur andnitrogen, or a bicyclic group comprising a 5-6 membered ring containingfrom one to four heteroatoms selected from oxygen, sulfur and nitrogenfused with a benzene ring or a 5-6 membered ring containing from one tofour heteroatoms selected from oxygen, sulfur and nitrogen, wherein theheteroaryl group in one embodiment of the invention may be optionallysubstituted by one or two substituents selected from halogen, amino orhydroxyl.

The term “halogen” represents fluorine, chlorine, bromine and iodine.

The term “analog” or “derivative” is used herein in the conventionalpharmaceutical sense, to refer to a molecule that structurally resemblesa reference molecule, but has been modified in a targeted and controlledmanner to replace one or more specific substituents of the referentmolecule with an alternate substituent, thereby generating a moleculewhich is structurally similar to the reference molecule. Synthesis andscreening of analogs (e.g. using structural or biochemical analysis) toidentify slightly modified versions of a known compound which may haveimproved properties (e.g. higher potency and/or selectivity at aspecific targeted receptor type, greater ability to penetrate into theeye, fewer side effects) is a typical drug design approach.

The invention also relates to a compound of formula (I), wherein

-   -   R¹ is hydrogen, —C₁₋₆-alkyl, —C(O)—R or —C(O)—OR;    -   R² is hydrogen or —C₁₋₆-alkyl;    -   R³ is —OR, —NHR or —NR₂;    -   R⁴ is hydrogen, halogen, cyano, trifluoromethyl, —C₁₋₆-alkyl;    -   R⁵ is hydrogen or —C₁₋₆-alkyl; in particular —C₁₋₃-alkyl;    -   R⁶ is hydrogen or —C₁₋₆-alkyl; in particular —C₁₋₃-alkyl; or    -   R⁵ and R⁶ together with the carbon atom carrying them form a        cyclic system with 3 to 6 carbon atoms;    -   R is hydrogen or —C₁₋₆-alkyl; in particular hydrogen or        —C₁₋₃-alkyl;    -   X is a group —C(O)CH₂—, —CH(OH)CH₂—, —CH═CH— or —CH₂NHC(O)—;    -   R⁷ is hydrogen or methyl;        or an optical isomer, pharmaceutically acceptable salt, hydrate,        solvate, or polymorph thereof.

The invention also relates to a compound of formula (I), wherein

-   -   R¹ is hydrogen, —C₁₋₃-alkyl, or —C(O)—CH₃;    -   R² is hydrogen or —C₁₋₃-alkyl;    -   R³ is —OR, —NHR or —NR₂;    -   R⁴ is hydrogen or halogen;    -   R⁵ is —C₁₋₃-alkyl;    -   R⁶ is —C₁₋₃-alkyl;    -   R is hydrogen or —C₁₋₃-alkyl;    -   X is a group —C(O)CH₂—, —CH(OH)CH₂—, —CH═CH— or —CH₂NHC(O)—;    -   R⁷ is hydrogen;        or an optical isomer, pharmaceutically acceptable salt, hydrate,        solvate, or polymorph thereof.

The invention also relates to a compound of formula (I), wherein

-   -   R¹ is hydrogen, —C₁₋₃-alkyl, or —C(O)—CH₃;    -   R² is hydrogen;    -   R³ is —OR —NHR;    -   R⁴ is hydrogen;    -   R⁵ is hydrogen or —C₁₋₃-alkyl;    -   R⁶ is hydrogen or —C₁₋₃-alkyl;    -   R is hydrogen or —C₁₋₃-alkyl;    -   X is a group —C(O)CH₂—, —CH(OH)CH₂—, —CH═CH— or —CH₂NHC(O)—;    -   R⁷ is hydrogen;        or an optical isomer, pharmaceutically acceptable salt, hydrate,        solvate, or polymorph thereof.

The invention also relates to a compound of formula (I), wherein

-   -   R¹ is hydrogen or —C(O)—CH₃;    -   R² is hydrogen;    -   R³ is —OR —NHR;    -   R⁴ is hydrogen;    -   R⁵ is —C₁₋₃-alkyl;    -   R⁶ is —C₁₋₃-alkyl;    -   R is hydrogen or —C₁₋₃-alkyl;    -   X is a group —C(O)CH₂—, —CH(OH)CH₂—, —CH═CH— or —CH₂NHC(O)—;    -   R⁷ is hydrogen;        or an optical isomer, pharmaceutically acceptable salt, hydrate,        solvate, or polymorph thereof.

In the compounds of formula (I)

-   -   the group R¹ often denotes hydrogen or —C(O)—CH₃.    -   the group R² often denotes hydrogen.    -   the group R³ often denotes —OH, —OCH₃ or —NH—CH₃.    -   the group R⁴ often denotes hydrogen.    -   the groups R⁵ and R⁶ often are identical, in particular they        denote —CH₃.    -   the group X represents —C(O)CH₂— or —CH(OH)CH₂— or —CH═CH— or        —CH₂NHC(O)— (the orientation of the group X being as indicated,        the left side connected with the amino-group carrying chiral        carbon atom).

The invention also relates to a compound of formula (I), wherein thegroup X represents —C(O)CH₂— or —CH(OH)CH₂— or —CH═CH— or an opticalisomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

The invention also relates to a compound of formula (I), wherein thechiral center carrying the amino group and the group X hasR-configuration or a pharmaceutically acceptable salt, hydrate, solvate,or polymorph thereof.

The invention also relates to a compound according to formula (I) ofclaim 1 and having one of the chemical names cited in the experimentalpart of this application or a pharmaceutically acceptable salt, hydrate,solvate, or polymorph thereof.

One further aspect of the invention are compounds of formula (I) asdescribed above or their optical isomers, pharmaceutically acceptablesalts, hydrates, solvates or polymorphs thereof for use as a medicament.The medicament can be prepared in different formulations and can be usedfor various therapeutical purposes.

One further aspect of the invention are compounds of formula (I) ortheir optical isomers, pharmaceutically acceptable salts, hydrates,solvates or polymorphs thereof for treating or preventing ofCNS-disorders, in particular of Alzheimers disease.

One further aspect of the invention are compounds of formula (I) asdescribed above or their optical isomers, pharmaceutically acceptablesalts, hydrates, solvates or polymorphs thereof for treating orpreventing a disorder or disease associated with an abnormalagglomeration or polymerization of Abeta peptides.

One further aspect of the invention are compounds of formula (I) ortheir optical isomers, pharmaceutically acceptable salts, hydrates,solvates or polymorphs thereof for treating or preventing an oculardisorder or disease, in particular glaucoma.

Another aspect of the invention are compounds of formula (I) or theiroptical isomers, pharmaceutically acceptable salts, hydrates, solvatesor polymorphs thereof for treating or preventing a disorder or diseaseselected from the group consisting of:

-   -   primary angle-closure glaucoma, secondary open-angle glaucoma,        wide-angle glaucoma, steroid-induced glaucoma, traumatic        glaucoma, pigmentary dispersion syndrome, pseudo exfoliation        syndrome, secondary angle-closure glaucoma, neovascular        glaucoma, uveitis and glaucoma, age-related macular        degeneration, diabetic retinopathy, degenerative optic        neuropathy and other eye pathologies characterized by a        progressive loss of vision.

The invention also covers a pharmaceutical composition for thetreatment, wherein the condition to be treated is selected from thegroup consisting of primary angle-closure glaucoma, secondary open-angleglaucoma, wide-angle glaucoma, steroid-induced glaucoma, traumaticglaucoma, pigmentary dispersion syndrome, pseudo exfoliation syndrome,secondary angle-closure glaucoma, neovascular glaucoma, uveitis andglaucoma, age-related macular degeneration, diabetic retinopathy,degenerative optic neuropathy and eye pathologies characterized by aprogressive loss of vision, leading finally to blindness. Such acomposition can be prepared to comprise a therapeutically effectiveamount of a compound of formula (I) either alone or in combination withat least one additional pharmaceutical agent which is effective intreating the optical condition.

According to the present invention, the modulators of the aggregation orpolymerization of β-amyloid peptides (Abeta peptides) of formula (I) canbe administered to provide neuroprotection and/or disease modificationalso for the following acute or chronic pathological conditions ordiseases:

-   -   Alzheimers disease, Creutzfeld-Jakob's syndrome/disease, bovine        spongiform encephalopathy (BSE), diseases involving β-amyloid        and/or tauopathy, motor neuron diseases, amyotrophic lateral        sclerosis (ALS), olivoponto-cerebellar atrophy, post-operative        cognitive deficit (POCD), systemic lupus erythematosus, systemic        clerosis, Sjogren's syndrome, Neuronal Ceroid Lipofuscinosis,        neurodegenerative cerebellar ataxias, Parkinson's disease,        Parkinson's dementia, cognitive impairment, cognitive deficits        in various forms of mild cognitive impairment, cognitive        deficits in various forms of dementia, dementia pugilistica,        vascular and frontal lobe dementia, cognitive impairment,        learning impairment, eye injuries, eye diseases, eye disorders,        glaucoma, retinopathy, macular degeneration, head or brain or        spinal cord injuries, head or brain or spinal cord trauma,        trauma, hypoglycaemia, hypoxia, perinatal hypoxia, ischaemia,        convulsions, epileptic convulsions, epilepsy, temporal lobe        epilepsy, myoclonic epilepsy, inner ear insult, tinnitus,        L-dopa-induced dykinesias, dyskinesias, chorea, Huntington's        chorea, athetosis, dystonia, stereotypy, ballism, tardive        dyskinesias, tic disorder, torticollis spasmodicus,        blepharospasm, focal and generalized dystonia, nystagmus,        hereditary cerebellar ataxias, corticobasal degeneration,        tremor, essential tremor, abuse, addiction, nicotine addiction,        nicotine abuse, alcohol addiction, alcohol abuse, opiate        addiction, opiate abuse, cocaine addiction, cocaine abuse,        amphetamine addiction, amphetamine abuse, anxiety disorders,        panic disorders, anxiety and panic disorders, social anxiety        disorder (SAD), attention deficit hyperactivity disorder (ADHD),        attention deficit syndrome (ADS), restless leg syndrome (RLS),        hyperactivity in children, autism, dementia, dementia in        Alzheimers disease, dementia in Korsakoff syndrome, Korsakoff        syndrome, vascular dementia, major depressive disorder,        depression, bipolar manic-depressive disorder, irritable bowel        syndrome (IBS), migraine, multiple sclerosis (MS), muscle        spasms, pain, chronic pain, acute pain, inflammatory pain,        schizophrenia, spasticity, Tourette's syndrome, sleep disorders,        anxiety disorder, obsessive-compulsive disorder, panic disorder,        posttraumatic stress disorder, social phobia, phobic disorders        and schizophreniform disorder, down syndrome, diabetis mellitus        (type II), familiar amyloid polyneuropathy and cerebrat amyloid        angiopathy.

Optionally, the composition may further comprise another activeingredient which is not a compound of formula (I). The invention alsorelates to a combination to be co-administered to the living human oranimal a therapeutically effective amount of a compound (I) as describedabove in combination with at least one additional pharmaceutical agentwhich is effective in treating e. g. a CNS-disorder or an ophthalmiccondition, wherein the combination of the compound (I) and the at leastone additional pharmaceutical agent is effective in treating thecondition.

The additional pharmaceutical substance is e.g. selected from drugcompounds administered to treat or prevent a CNS-disorder (such asAlzheimers) or to treat ocular diseases. Typical combination drugs areanti-Alzheimer drugs, anti-glaucoma drugs, antibiotics,anti-inflammatory drugs, steroids, anti-allergic drugs and artificialtear fluid.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising at least two different active ingredients, wherethe composition contains at least one compound of formula (I) as definedabove or an optical isomer, pharmaceutically acceptable salt, hydrate,solvate or polymorph thereof, and contains at least one further activeingredient, and one or several pharmaceutically acceptable excipients.The two active ingredients (drug compounds) can in principal beadministered together or separately. Such a further additional activeingredient (drug compound) is e. g. selected from:

-   -   acetazolamide, diclofenamide, carteolol, timolol, metipranolol,        betaxolol, pindolol, levobundolol, brimonidine, clonidine,        pilocarpine, carbachol, dipivefrine, apraclonidine,        brinzolamide, dorzolaminde, bimatroprost, travaprost,        latanoprost, chlortetracycline, ciprofloxacine, ofloxacine,        fusidinic acid, gentamicine, kanamycine, levofloxacine,        lomefloxacine, oxytetracycline, natamycine, azidamfenicole,        chloramphenicole, tobramycine, erythromycin, polymyxin-B,        acaclovir, trifluridine, betamethasone, dexamethasone,        fluorometholone, hydrocortisone, prednisolone, rimexolone,        cromoglicate, azelastine, lodoxamide, emedastine, nedocromile,        levocabstine, olopatadinea, ketoifene, hyaluronate,        dexpanthenole, tetryzoline, troxerutine, tramazoline,        naphazoline, xylometazoline, phenylephrine and antazoline.

For CNS-application, the additional drug compound is e.g. selected frommemantine, galantamine, donepezile and rivastigmine. Of particularinterest are combinations of a compound of formula (I) with memantine.

The compound of formula (I) or the combination product is e.g.administered once a day, twice a day or three times a day. Often it isadministered chronically. In one embodiment, the composition isadministered in the form of eye drops, eye creams, and intraocular depotformulations. The composition can also be administered in an immediateor modified release formulation. The compound of formula (I) and theadditional pharmaceutical agent can be administered separately orconjointly.

These compounds of formula (I) are preferably administered in the formof a pharmaceutical composition, which is easily to ply to a person oranimal, wherein the compounds of formula (I) are present together withone or several pharmaceutically acceptable diluents, carriers, orexcipients.

It is one further aspect of the invention, to provide a pharmaceuticalcomposition comprising as active ingredient at least one compound offormula (I) as defined above or an optical isomer, pharmaceuticallyacceptable salt, hydrate, solvate or polymorph thereof, together withone or several pharmaceutically acceptable excipients.

It is a further object of the invention to provide a novel method oftreating, eliminating, alleviating, palliating, or amelioratingundesirable CNS disorders which involve modulation of Abetapolymerization by employing a compound of formula (I) or apharmaceutical composition containing the same.

An additional object of the invention is the provision of processes forpreparing the indole derivatives. The invention therefore relates to aprocess for the preparation of a compound of formula (I),

wherein

-   -   R¹ is hydrogen, —C₁₋₆-alkyl, cycloC₃₋₁₂-alkyl, —C(O)—R or        —C(S)—R;    -   R² is hydrogen, —C₁₋₆-alkyl or cycloC₃₋₁₂-alkyl;    -   R³ is —OR, —NHR or —NR₂;    -   R⁴ is hydrogen, halogen, cyano, trifluoromethyl, nitro,        —C₁₋₆-alkyl, —C₆₋₁₀-aryl, heteroaryl, —OR, —NHR, —NRR, —C(O)—R        or —C(O)—NHR;    -   R⁵ is hydrogen, —C₁₋₆-alkyl or C₂₋₆-alkenyl;    -   R⁶ is hydrogen, —C₁₋₆-alkyl or C₂₋₆-alkenyl; or    -   R⁵ and R⁶ together with the carbon atom carrying them form a        cyclid system with 3 to 6 carbon atoms;    -   R is hydrogen or —C₁₋₆-alkyl;    -   X is a group —C(O)CH₂—, —CH(OH)CH₂—, —CH═CH— or —CH₂—NH—C(O)—;    -   R⁷ is hydrogen, methyl, ethyl, propyl or cyclopropyl;        comprising the step of starting from an intermediate a compound        of formula (II)

-   -   wherein    -   X_(a) is a carbonyl function carrying group, such as —CHO,    -   and the other radicals are defined as above,    -   which then is transformed in one ore several steps, preferably        in the presence of a condensing agent, to yield a compound of        formula (I), which then is converted, if desired, to a        pharmaceutically acceptable salt, hydrate, solvate, or        polymorph.

Furthermore, the preparation of optical isomers, pharmaceuticallyacceptable salts, hydrates, solvates, and polymorphs of a compounds offormula (I) is part of the invention. Also, the manufacturing orpreparation of a medicament is part of the invention.

The invention also relates to compounds of the formula (I) which aremarked by radioactive atoms. Typical compounds include those where oneor more hydrogens are substituted by tritium, where one or more C¹² aresubstituted by C¹⁴, where one or more fluor atoms are substituted by F¹⁸or other isotopes. These can be used for the treatment of diseases (e.g.cancer) but also for diagnostic purposes. The radioactive atomsexchanged in the molecule are often isotopes of carbon, hydrogen,halogen, sulphur or phosphor.

The invention in general relates to the use of modulators of thepolymerization of Abeta peptides for the preparation of a medicament andfor the treatment of various diseases as mentioned above in a mammal,including humans.

The invention also relates to an intermediate compound of formula (II)

wherein X_(a) is a carbonyl function carrying group, e.g. —CHO.

The invention also relates to a process of preparation, where thecompound of formula (I) is prepared in an enantio-selective reaction,preferably leading to the R-configurated compound.

Moreover, the modulators of the polymerization of Abeta peptides offormula (I) as described above have a high activity when administered incombination with other substances exhibiting neurological effects viadifferent mechanisms. The invention also relates to a pharmaceuticalcomposition comprising at least two different active ingredient,containing at least one compound of formula (I) as defined above, andfurthermore containing at least one NMDA-antagonist, together with oneor more pharmaceutically acceptable excipients. These compositions canbe used for the treatment of CNS-related diseases, cognitive enhancementand for neuro-protection. Simultaneous administration of modulators ofthe polymerization of Abeta peptides and NMDA receptor antagonists canprovide neuroprotection in animal models.

With respect to the compounds of formula (I) as described above, thecombined therapy exhibits a greater neuroprotective effect thanmonotherapy with either an modulator of the polymerization of Abetapeptides or an NMDA receptor antagonist. As particularly active NMDAreceptor antagonist, the compound Memantine can be named, which is alsoknown as 1-Amino-3,5-dimethyladamantane (see U.S. Pat. Nos. 4,122,193;4,273,774; and 5,061,703).

Memantine is a systemically-active noncompetitive NMDA receptorantagonist having moderate affinity for the receptor. The combination ofNMDA antagonists with modulators of formula (I) can be realized in asingle pharmaceutical composition (as principally described in the priorart) comprising a compound of formula (I) of the present invention andan NMDA receptor antagonist, in one pharmaceutical formulation, or intwo separate pharmaceutical compositions or formulations, one comprisinga compound of formula (I) of the present invention and one comprising anNMDA receptor antagonist in a pharmaceutical formulation, to beadministered conjointly (simultaneously or sequentially). For thesequential administration to be considered “conjoint”, however, thecompound of formula (I) of the present invention and the NMDA receptorantagonist must be administered separated by a time interval that stillpermits the resultant beneficial effect in a mammal. For example, thecompound of formula (I) and the NMDA receptor antagonist must beadministered on the same day (e.g., each—once or twice daily),preferably within an hour of each other, and most preferablysimultaneously.

The following Scheme describes the preparation of compounds of formula(I) of the present invention. All of the starting materials may beprepared by procedures described in these schemes, by procedures wellknown to one of ordinary skill in organic chemistry, or may be obtainedcommercially. All of the final compounds of the present invention may beprepared by procedures described in these charts or by proceduresanalogous thereto, which would be well known to one of ordinary skill inorganic chemistry. All of the variables used in the schemes are asdefined below or as in the claims. The compounds containing one or morechiral centers can be prepared as racemates or mixtures of variousstereoisomers and then separated. However, they also can be prepared bya special enantioselective synthesis. For several of the chiralcompounds, the enantiomers differ in pharmacological activity.

The indole compounds of the present invention may be synthesized bydifferent synthetic routes by using reactions principally known to theskilled chemist.

Some preferred methods of preparation of the compounds of formula (I)

depending on whether the spacer element Xis a group

-   -   —C(O)CH₂—,    -   —CH(OH)CH₂—,    -   —CH═CH— or    -   —CH₂—NH—C(O)—        are summarized in the following general Scheme I

wherein

-   X_(a) is e.g. —CHO (or —CH₂—NH₂);-   X_(b) is e.g. (Ph)₂P(O)CH₂—, with Ph being Phenyl, (or —COOH);-   R⁸ is e.g. —CH₂O-TBS or CH₂O—Si(alkyl)₃, with TBS being    tributylsilyl, (or —COOCH₃).    Scheme II shows a method for preparing compounds of the type of    examples 6 to 14.

Scheme III shows a method for preparing compounds of the type of example1.

The pure stereoisomeric forms (and in particular optical isomers) of thecompounds and the intermediates of this invention may be obtained by theapplication of art-known procedures. Diastereomers may be separated byphysical separation methods such as selective crystallization andchromatographic techniques, e.g. liquid chromatography using chiralstationary phases. Enantiomers (optically active isomers) may beseparated from each other by selective crystallization of theirdiastereomeric salts with optically active acids. Alternatively,enantiomers may be separated by chromatographic techniques using chiralstationary phases.

Said pure stereoisomeric forms may also be derived from thecorresponding pure stereoisomeric form of appropriate startingmaterials, provided that the reaction occur stereoselectively.Stereoisomeric forms of formula (I) are included within the scope ofthis invention.

For therapeutic uses, the salts of the compounds of formula (I) arethose wherein the counterion is pharmaceutically acceptable. However,salts of acids (and bases), which are non-pharmaceutically acceptable,may also find use, for example, in the preparation and purification ofpharmaceutically acceptable compounds. All salts whetherpharmaceutically acceptable or not are included in the presentinvention. The pharmaceutically acceptable salts as mentioned above aremeant to comprise the therapeutically active non-toxic salt forms, whichthe compounds of formula (I) are able to form. The latter canconveniently be obtained by treating the base form with such appropriateacids as inorganic acids, e.g. hydrohalic acids such as hydrochloric,hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acidand the like; or organic acids such as acetic, propanoic, hydroxyacetic,2-hydroxypropanoic, oxopropanoic, oxalic, malonic, succinic, maleic,fumaric, malic, tartaric, 2-hydroxy-1,2,3-propanetricarboxylic,methanesulfonic, ethanesulfonic, benzenesulfonic,4-methylbenzene-sulfonic, cyclohexanesulfonic, 2-hydroxybenzoic,4-amino-2-hydroxybenzoic and the like acids. Conversely, the salt formcan be converted by treatment with alkali into the free base form.

Preparation of Pharmaceutical Compositions

The active ingredients of formula (I) of the invention, together withone or more conventional excipients (adjuvants, carriers, or diluents)may be placed into the form of pharmaceutical compositions and unitdosages thereof. The compositions may be employed as solids, such ascoated or uncoated tablets or filled capsules, or liquids, such assolutions, suspensions, emulsions, or capsules filled with the same. Thecompositions can be prepared for oral use.

They can be in the form of suppositories or capsules for rectaladministration.

Compositions can be in the form of sterile injectable solutions forparenteral (including intravenous or subcutaneous) use. They can be inliquid or semi-liquid form for ophthalmic application to the eye.

Such pharmaceutical compositions and unit dosage forms thereof maycomprise conventional or new ingredients in conventional or specialproportions, with or without additional active compounds. Such unitdosage forms may contain any suitable effective amount of the activeingredient of formula (I) commensurate with the intended daily dosagerange to be employed.

Compositions containing 0.5 to 1000 milligrams, preferably 1 to 100milligrams of active ingredient per application unit are suitablerepresentative unit dosage forms.

The term “excipient” applied to pharmaceutical compositions of theinvention refers to a diluents, adjuvants or carrier with which anactive compound of formula (I) is administered. Such pharmaceuticalexcipients often are sterile liquids, such as water or saline solutions.Other excipients, depending on the type of administration, can beaqueous dextrose solutions, aqueous glycerol solutions, and oils,including those of animal, vegetable or synthetic origin (see A. R.Gennaro, 20^(th) Edition, “Remington: The Science and Practice ofPharmacy”).

Due to their high degree of activity and their low toxicity, togetherpresenting a favorable therapeutic index, the compounds of formula (I)may be administered to a subject, e.g., a living mammal (including ahuman) body, for the treatment, alleviation, or amelioration,palliation, or elimination of an indication or condition which issusceptible thereto, or representatively of an indication or conditionset forth elsewhere in this application, preferably concurrently,simultaneously, or together with one or more pharmaceutically-acceptableexcipients, especially in the form of a pharmaceutical compositionthereof, whether by oral, rectal, parental or topical route, in aneffective amount. Suitable dosage ranges are 1 to 1000 milligrams daily,preferably 5 to 500 milligrams daily, and especially 10 to 500milligrams daily, depending as usual upon the exact mode ofadministration, form in which administered, the indication toward whichthe administration is directed, the subject involved and the body weightof the subject involved, and the preference and experience of thephysician or veterinarian in charge. The term “therapeuticallyeffective” applied to dose or amount refers to that quantity of acompound or pharmaceutical composition that is sufficient to result in adesired activity upon administration to a living animal body in needthereof.

The compounds of formula (I) of the present invention may beadministered orally, topically, parenterally, or mucosally (e.g.,buccally, by inhalation, or rectally) in dosage unit formulationscontaining conventional non-toxic pharmaceutically acceptableexcipients. For ophthalmological applications (for ocular diseases anddisorders), topic formulations are often applied. They are often waterbased solutions or dispensions.

The compound of formula (I) can also be administered orally in the formof a capsule, a tablet, or the like (see Remington: The Science andPractice of Pharmacy, 20^(th) Edition). The orally administeredcompositions can be administered in the form of a time-controlledrelease vehicle, including diffusion-controlled systems, osmoticdevices, dissolution-controlled matrices, and erodible/degradablematrices.

For oral administration in the form of a tablet or capsule, the compoundof formula (I) may be combined with non-toxic, pharmaceuticallyacceptable excipients such as binding agents (e.g., pregelatinized maizestarch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers(e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducingand non-reducing sugars, microcrystalline cellulose, calcium sulfate, orcalcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc,or silica, steric acid, sodium stearyl fumarate, glyceryl behenate,calcium stearate, and the like); disintegrants (e.g., potato starch orsodium starch glycolate); or wetting agents (e.g., sodium laurylsulphate), coloring and flavoring agents, gelatin, sweeteners, naturaland synthetic gums (such as acacia, tragacanth or alginates), buffersalts, carboxymethylcellulose, polyethyleneglycol, waxes, and the like.The tablets containing a compound of formula (I) may be coated bymethods well known in the art.

For oral administration in liquid form, the drug components may becombined with non-toxic, pharmaceutically acceptable inert carriers orsolvents (e.g., ethanol, glycerol, water), suspending agents (e.g.,sorbitol syrup, cellulose derivatives or hydrogenated edible fats),emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles(e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetableoils), preservatives (e.g., methyl or propyl-p-hydroxybenzoates orsorbic acid), and the like. Stabilizing agents such as antioxidants(BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also beadded to stabilize the dosage forms.

The compositions of the invention containing a compound of formula (I)may be also introduced in beads, microspheres or microcapsules, e.g.,fabricated from polyglycolic acid/lactic acid (PGLA). Liquidpreparations for oral administration may take the form of solutions,syrups, emulsions or suspensions, or they may be presented as a dryproduct for reconstitution with water or other suitable vehicle beforeuse. Preparations for oral administration may be suitably formulated togive controlled or postponed release of the active compound.

The active drugs of formula (I) may also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines, as is well known.

The active compound of formula (I) may also be coupled with solublepolymers as targetable drug carriers. Such polymers includepolyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propylmethacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, orpolyethyleneoxide-polylysine substituted with palmitoyl residues.Furthermore, the compound of formula (I) may be coupled to a class ofbiodegradable polymers useful in achieving controlled release of a drug,for example, polylactic acid, polyglycolic acid, copolymers ofpolylactic and polyglycolic acid, polyepsilon caprolactone,polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans,polycyanoacrylates, and cross-linked or amphipathic block copolymers ofhydrogels.

For administration by inhalation, the therapeutics according to thepresent invention containing as active compound a compound of formula(I) may be conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g. dichlorodifluoromethane or other suitable gas.

The formulations of the invention containing a compound of formula (I)may be delivered parenterally, i.e., by intravenous (i.v.),intracerebroventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal(i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.)administration, by direct injection, e.g. via bolus injection orcontinuous infusion.

Formulations for injection (in particular for application to the eye)can be presented in unit dosage form, e.g., in ampoules or in multi-dosecontainers, with an added preservative. The compositions can be asuspension, solutions, or emulsion e.g. in aqueous vehicles, and cancontain excipients such as suspending, stabilizing and/or dispersingagents. Alternatively, the compound of formula (I) can be in powder formfor reconstitution with a suitable excipient, e.g., sterile pyrogen-freewater, for reconstitution.

Compositions of the present invention containing a compound of formula(I) may also be formulated for rectal administration, e.g., assuppositories or retention enemas (e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides).

The compositions containing a compound of formula (I) may be presentedin a pack or dispenser device, which may contain one or more unit dosageforms containing the active ingredient and/or may contain differentdosage levels to facilitate dosage titration. The pack may comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.Compositions of the invention formulated in a compatible pharmaceuticalcarrier may also be prepared, placed in an appropriate container, andlabeled for treatment of an indicated condition.

As disclosed herein, the dose of the components in the compositions ofthe present invention is determined to ensure that the dose administeredcontinuously or intermittently will not exceed an amount determinedafter consideration of the results in test animals and the individualconditions of a patient. A specific dose naturally varies depending onthe dosage procedure, the conditions of a patient or a subject animalsuch as age, body weight, sex, sensitivity, feed, dosage period, drugsused in combination, seriousness of the disease. The appropriate doseand dosing times under certain conditions can be determined by the testbased on the above-described indices but may be refined and ultimatelydecided according to the judgment of the practitioner and each patient'scircumstances (age, general condition, severity of symptoms, sex, etc.)according to standard clinical techniques.

Toxicity and therapeutic efficacy of the compositions of the inventioncan be determined by standard pharmaceutical procedures in experimentalanimals, e.g., by determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between therapeutic and toxic effects isthe therapeutic index and it may be expressed as the ratio ED₅₀/LD₅₀.Those pharmaceutical compositions that exhibit large therapeutic indicesare preferred.

EXAMPLES

With the aid of commonly used solvents and excipients, the compounds offormula (I) can be brought into a liquid formulation or be processedinto tablets, coated tablets, capsules, drip solutions, suppositories,injection and infusion preparations, and can be therapeutically appliedby the topical, oral, rectal, parenteral, and additional routes.

For topical (including ophthalmic) sterile solutions, the compound offormula (I) together with conventional excipients in usual amounts areemployed, such as for example sodium chloride and double-distilled waterq.s., according to conventional procedure, such as filtration, asepticfilling into ampoules, and if necessary autoclaving for sterility.

A) Preparation of Indole-Derivatives Example 1 Synthesis of Compound(121)

The Compound (121) was prepared according to the following steps:

a) Compound 22

A solution of compound 1 (10.0 g, 33 mmol) and THF (50 mL) was cooled to0° C. under N₂ atmosphere, then BH₃/THF was added dropwise. Thetemperature of the reaction mixture was allowed warm to roomtemperature. After stirring for 16 hours, the reaction mixture wasquenched by K₂CO₃ (aq.), extracted with EtOAc (100 mL×3), the combinedorganic phase was washed with brine (50 mL) dried over Na₂SO₄,concentrated in vacuo and purified with column (PE/EtOAc=4:1) to givethe product 22 as white solid (5.72 g, 60% yield). ¹H NMR (400 MHz,CDCl₃): δ 1.46 (s, 9H), 3.02 (d, J=6.8 Hz, 2H), 3.80-3.55 (m, 2H),4.10-3.95 (m, 1H), 4.86 (br s, 1H), 7.07 (s, 1H), 7.16 (t, J=7.2 Hz,1H), 7.23 (t, J=7.2 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.68 (d, J=7.6 Hz,1H), 8.20 (s, 1H).

b) Compound 23

To a stirred solution of compound 22 (4.0 g, 14 mmol) in DCM (10 mL) wasadded DMSO (15 mL) and Et₃N (3.23 g, 32 mmol). The mixture was cooled to0° C., and then a solution of SO₃.Py (4.83 g, 30 mmol) in DMSO (15 mL)was added dropwise under N₂ atmosphere. After stirring for 1 hour atroom temperature, the mixture was poured into ice/water (20 mL), andextracted with EtOAc (100 mL×3), the combined organic phase was washedwith brine (50 mL), dried over Na₂SO₄ and concentrated in vacuo to givethe crude product without purification (2.86 g, 71% yield). ¹H NMR (400MHz, DMSO-d₆): δ 1.37 (s, 9H), 3.02-2.85 (m, 1H), 3.20-3.12 (m, 1H),4.14-4.05 (m, 1H), 4.20-4.06 (m, 1H), 7.00 (t, J=7.4 Hz, 1H), 7.08 (t,J=7.4 Hz, 1H), 7.17 (s, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.52 (d, J=7.6 Hz,1H), 9.55 (s, 1H), 10.88 (s, 1H).

c) Compound 24

To a stirred solution of compound 23 (500 mg, 1.7 mmol) in DCM (25 mL)was added BnNH₂ (214 mg, 2.0 mmol) and NaBH(OAc)₃ (1.1 g, 5.2 mmol).After stirring for 16 hours at room temperature, the mixture was pouredinto ice/water (20 mL) and extracted with DCM/MeOH (10:1, 20 mL×3). Thecombined organic phase was washed with brine (50 mL), dried over Na₂SO₄and concentrated in vacuo. The residue was purified with Prep-TLC(DCM/MeOH=20/1) to give the product 24 as white solid (370 mg, 56%yield).

d) Compound 25

To a stirred solution of compound 24 (150 mg, 0.4 mmol) in MeOH (10 mL)was added Pd(OH)₂ (50 mg) and HOAc (catalyst). After stirring for 16hours at room temperature under H₂ atmosphere, the mixture was pouredinto water (50 mL) and extracted with DCM/MeOH (10:1, 20 mL×3), thecombined organic phase was washed with brine (50 mL), dried over Na₂SO₄and concentrated in vacuo, the residue was purified with Prep-TLC(DCM/MeOH=30/1) to give the product 25 as white solid (83 mg, 70%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 1.37 (s, 9H), 3.02-2.85 (m, 1H),3.20-3.12 (m, 1H), 4.14-4.05 (m, 1H), 4.20-4.06 (m, 1H), 7.00 (t, J=7.4Hz, 1H), 7.08 (t, J=7.4 Hz, 1H), 7.17 (s, 1H), 7.54 (d, J=7.6 Hz, 1H),7.52 (d, J=7.6 Hz, 1H), 9.55 (s, 1H), 10.79 (s, 1H).

e) Compound 26

To a stirred solution of compound 25 (350 mg, 1.20 mmol) in DMF (10 mL)was added 2-(methoxycarbonyl)-2-methylpropanoic acid (256 mg, 1.6 mmol),HOBt (243 mg, 1.8 mmol), EDC (607 mg, 2.5 mmol) and DIEA (774 mg, 6.0mmol). After stirring for 16 hours at room temperature under N₂atmosphere, the mixture was poured into water (50 mL) and extracted withEtOAc (20 mL×3). The organic phase was washed with brine (50 mL), driedover Na₂SO₄, concentrated in vacuo and the residue purified withPrep-TLC (DCM/MeOH=30/1) to give the product 26 as white solid (338 mg,67% yield).

f) Compound 27

To a stirred solution of compound 26 (417 mg, 1 mmol) in MeOH/H₂O (5:2.7 mL) was added LiOH.H₂O (168 mg, 4 mmol), After stirring for 4 hours atroom temperature, HCl (con.) was added to the mixture to make PH to 5,extracted with EtOAc (20 mL×3), The combined organic phase was washedwith brine (50 mL), dried over Na₂SO₄ and concentrated in vacuo to givethe product 27 as white solid (256 mg, 81% yield).

g) Compound 121

A solution of compound 27 (200 mg, 0.500 mmol) in EtOAc/HCl (20 mL, 4 M)was stirred for 2 hours at room temperature, then concentrated in vacuoto give the product 121 as white solid (136 mg, 80% yield). ¹H NMR (400MHz, DMSO-d₆): δ 1.32 (s, 6H), 3.20-2.85 (m, 2H), 3.50-3.25 (m, 3H),7.02 (t, J=7.2 Hz, 1H), 7.11 (t, J=7.2 Hz, 1H), 7.28 (s, 1H), 7.38 (d,J=7.6 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 9.50-7.90 (m, 4H), 11.04 (s, 1H).LCMS [mobile phase: from 95% water (0.02% NH₄Ac) and 5% CH₃CN to 40%water (0.02% NH₄Ac) and 60% CH₃CN in 6 min, finally under theseconditions for 0.5 min.] purity is 98.3%, Rt=2.974 min; MS Calcd.:303.1; MS Found: 304.1 ([M+1]⁺).

Example 2 Synthesis of Compound (171)

The Compound (171) was prepared according to the following steps:

a) Compound 29

To a stirred solution of compound 28 (20.0 g, 0.12 mol) in DCM (200 mL)was added TBSC1 (21.8 g, 0.14 mol), Et₃N (20.2 g, 0.20 mol) and DMAP(8.0 g, 65.2 mmol). The mixture was stirred for 16 hours at roomtemperature, then concentrated in vacuo and purified with column (PE) togive the product (32.0 g, 95% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 0.08(s, 6H), 0.92 (s, 9H), 1.00 (s, 6H), 3.40 (s, 4H)

b) Compound 31

A solution of compound 30 (3.31 g, 17.8 mmol) in THF (10 mL) was cooledto −78° C., then BuLi (2.5M in hexane, 9.3 mL, 23.1 mmol) was addeddropwise. After stirring for 1 hour at the same temperature, thencompound 29 (4.98 g, 17.8 mmol) was added dropwise at −78° C. Thereaction mixture was allowed to warm to room temperature. After stirringfor 3 hours, the reaction mixture was quenched with NH₄Cl (sat., 20 mL),extracted with EtOAc (200 mL). The organic phase was washed with brine(50 mL), dried over Na₂SO₄ and concentrated in vacuo and the residue waspurified with column (PE:EtOAc=4:1) to give the product 31 (4.20 g, 60%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 0.03 (s, 6H), 0.92 (s, 9H), 1.04(s, 6H), 2.44 (d, J=10.8 Hz, 2H), 3.31 (s, 2H), 7.50-7.45 (m, 6H),7.86-7.70 (m, 4H).

c) Compound 32

To a stirred solution of compound 1 (3.04 g, 10.0 mmol) in DMF (20 mL)was added N-Methoxy-N-methylamine Hydrochloride (1.95 g, 20.0 mmol),HOBt (1.35 g, 10.0 mmol), EDC (2.90 g, 15.0 mmol) and DIEA (774 mg, 6.0mmol). After stirring for 16 hours at room temperature under N₂atmosphere, the mixture was poured into H₂O (100 mL) and was extractedwith EtOAc (40 mL×3). The combined organic phase was washed with brine(50 mL) dried over Na₂SO₄ and concentrated in vacuo and the residue waspurified with column (PE:EtOAc=6:1) to give the product 32 as whitesolid (3.06 g, 88% yield).

d) Compound 33

To a stirred solution of compound 32 (6.50 g, 18.7 mmol) in DCM (100 mL)was added Boc₂O (8.20 g, 37.4 mmol), DMAP (1 g, 8.2 mmol) and DIEA (2.58g, 20 mmol). After stirring for 16 hours at room temperature under N₂atmosphere, the mixture was poured into H₂O (100 mL) and was extractedwith EtOAc (100 mL×3), washed with brine (100 mL), dried over Na₂SO₄ andconcentrated in vacuo and the residue was purified with column (PE:EtOAc=10:1) to give the product 33 (7.30 g, 87% yield). ¹H NMR (400 MHz,DMSO-d₆): δ 1.43 (s, 9H), 1.70 (s, 9H), 3.20-3.01 (m, 5H), 3.73 (s, 1H),5.40-5.00 (m, 1H), 7.35-7.20 (m, 2H), 7.46 (s, 1H), 7.56 (d, J=7.2 Hz,1H), 8.14 (br s, 1H)

e) Compound 34

A mixture of LAH (111 mg, 2.9 mmol) in THF (10 mL) was cooled to −78°C., then a solution of compound 33 (1.0 g, 2.2 mmol) in THF (10 mL) wasadded dropwise slowly. After stirring for 2 hours at 0° C., the reactionmixture was quenched by KHSO₄ (sat.) and extracted with EtOAc (20 mL×3).The combined organic phase was washed with HCl (1N)(50 mL×2) and brine(50 mL), dried over Na₂SO₄ and concentrated in vacuo to give the crudeproduct 34 (609 mg, 70% yield).

f) Compound 35

A solution of compound 31 (4.2 g, 10.3 mmol) in THF (50 mL) was cooledto −78° C., then BuLi (2.5 M in hexane, 4.5 mL, 11.3 mmol) was addeddropwise and the mixture was stirred for 1 hour at the same temperature,then a solution of compound 34 (4.0 g, 10.3 mmol) in THF (10 mL) wasadded dropwise at −78° C. The reaction mixture was allowed to warm toroom temperature. After stirring for 3 hours, the reaction mixture wasquenched with NH₄Cl (sat., 20 mL), extracted with EtOAc (200 mL), theorganic phase was washed with brine (50 mL), dried over Na₂SO₄,concentrated in vacuo and the residue was purified with column (PE:EtOAc=10:1) to give the product 35 (1.0 g, 17% yield). ¹H NMR (400 MHz,DMSO-d₆): δ 0.01 (s, 6H), 0.93-0.85 (m, 15H), 1.28 (s, 9H), 1.68 (s,9H), 3.00-2.90 (m, 2H), 3.27 (s, 1H), 4.61-4.50 (m, 2H), 5.39 (dd,J=15.6, 5.6 Hz, 1H), 5.57 (d, J=16.0 Hz, 1H), 7.36-7.20 (m, 2H), 7.41(s, 1H), 7.57 (d, J=7.6 Hz, 1H), 8.20-8.10 (m, 1H).

g) Compound 36

To a solution of compound 35 (1 g, 1.8 mmol) in THF (10 mL) was addedTBAF (913 mg, 3.49 mmol), After stirring for 3 hours at roomtemperature, the mixture was poured into water (50 mL) and extractedwith EA (50 mL×3), the combined organic phase was washed with brine (50mL), dried over Na₂SO₄, concentrated in vacuo and the residue waspurified with column (PE: EtOAc=4:1) to give the product 36 (721 mg, 90%yield).

h) Compound 37

To a solution of compound 36 (459 mg, 1.00 mmol) in DMF (10 mL) wasadded PDC (1.90 g, 5.00 mmol). After stirring for 24 hours at roomtemperature, the mixture was poured into water (50 mL) and extractedwith EtOAc (50 mL×3), the combined organic phase was washed with brine(50 mL), dried over Na₂SO₄, concentrated in vacuo and the residue waspurified with column (PE: EtOAc=8:1) to give the product 37 (396 mg, 86%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 1.12 (s, 3H), 1.18 (s, 3H), 1.32(s, 9H), 1.62 (s, 9H), 2.80-2.70 (m, 2H), 4.28-4.15 (m, 2H), 5.61 (dd,J=15.6, 6.0 Hz, 1H), 5.65 (d, J=16.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H),7.33-7.20 (m, 2H), 7.43 (s, 1H), 7.63 (d, J=7.2 Hz, 1H), 8.04 (d, J=7.6Hz, 1H), 12.24 (br s, 1H).

i) Compound 171

A solution of compound 37 (236 mg, 0.5 mmol) in EtOAc/HCl (10 mL, 4 M)was stirred for 2 hours at room temperature, then concentrated in vacuoand purified by Prep-HPLC to give the TFA salt of product 171 as whitesolid (201 mg, 75% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 1.03 (s, 3H),1.14 (s, 3H) 3.25-2.85 (m, 2H), 4.5-3.85 (m, 1H), 5.48 (dd, J=16.0, 8.0Hz, 1H), 5.80 (d, J=16.4 Hz, 1H), 7.18-6.99 (m, 3H), 7.37 (d, J=8.0 Hz,1H), 7.54 (d, J=7.6 Hz, 1H), 8.20-7.90 (br s, 3H), 10.98 (s, 1H), 12.41(br s, 1H). LCMS [mobile phase: from 95% water (0.02% NH₄Ac) and 5%CH₃CN to 40% water (0.02% NH₄Ac) and 60% CH₃CN in 6 min, finally underthese conditions for 0.5 min.] purity is >95%, Rt=3.127 min; MS Calcd.:272.1; MS Found: 273.1 ([M+1]⁺).

Examples 3 and 4 Synthesis of Compounds (172) and (173)

The Compounds (172) and (173) was prepared according to the followingsteps:

a) Compound 38

To a solution of compound 37 (100 mg, 0.20 mmol) in DMF (10 mL) wasadded NH₄Cl (54 mg, 1.0 mmol), HOBt (57 mg, 0.40 mmol), EDC (96 mg, 0.50mmol) and DIEA (258 mg, 2.0 mmol). After stirring for 16 hours at roomtemperature under N₂ atmosphere, the mixture was poured into H₂O (50 mL)and extracted with EtOAc (20 mL×3). The combined organic phase waswashed with brine (50 mL), dried over Na₂SO₄ and concentrated in vacuo,the residue was purified with Prep-TLC (PE/EtOAc=1/1) to give theproduct 38 as white solid (77 mg, 78% yield).

b) Compound 39

To a solution of compound 37 (100 mg, 0.20 mmol) in DMF (10 mL) wasadded methylamine hydrochloride salt (68 mg, 1.0 mmol), HOBt (57 mg,0.40 mmol), EDC (96 mg, 0.50 mmol) and DIEA (258 mg, 2.0 mmol). Afterstirring for 16 hours at room temperature under N₂ atmosphere, themixture was poured into H₂O (50 mL) and extracted with EtOAc (20 mL×3).The combined organic phase was washed with brine (50 mL), dried overNa₂SO₄ and concentrated in vacuo, the residue was purified with Prep-TLC(PE/EtOAc=2/1) to give the product 39 as white solid (82 mg, 84% yield).

c) Compound 172

A solution of compound 38 (0.4 mmol) in EtOAc/HCl (10 mL, 4.0 M) wasstirred for 2 hours at room temperature, the reaction mixture wasconcentrated in vacuo and the residue was purified by Prep-HPLC to giveHCl salt of 172 (52 mg, 42% yield) as white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 1.00 (s, 3H), 1.10 (s, 3H), 3.20-2.95 (m, 2H), 3.90-3.42 (m,1H), 5.51 (dd, J=15.6, 8.0 Hz, 1H), 5.79 (d, J=15.6 Hz, 1H), 6.76 (s,1H), 6.90 (s, 1H), 7.20-6.99 (m, 3H), 7.36 (d, J=8.0 Hz, 1H), 7.57 (d,J=7.6 Hz, 1H), 8.20-7.95 (br s, 3H), 10.98 (s, 1H). LCMS [mobile phase:from 95% water (0.05% TFA) and 5% CH₃CN to 5% water (0.05% TFA) and 95%CH₃CN in 6 min, finally under these conditions for 0.5 min.] purityis >95%, Rt=2.552 min; MS Calcd.: 271.1; MS Found: 272.1 ([M+1]⁺).

d) Compound 173

A solution of compound 39 (0.4 mmol) in EtOAc/HCl (10 mL, 4.0 M) wasstirred for 2 hours at room temperature, the reaction mixture wasconcentrated in vacuo and the residue was purified by Prep-HPLC to giveHCl salt of 172 (51 mg, 40% yield) as white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 1.00 (s, 3H), 1.10 (s, 3H) 2.51 (s, 3H), 3.20-2.90 (m, 2H),3.95-3.80 (m, 1H), 5.51 (dd, J=15.6, 8.0 Hz, 1H), 5.74 (d, J=15.6 Hz,1H), 7.20-6.99 (m, 4H), 7.36 (d, J=8.0 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H),8.25-8.10 (br s, 3H), 11.00 (s, 1H). LCMS [mobile phase: from 95% water(0.05% TFA) and 5% CH₃CN to 5% water (0.05% TFA) and 95% CH₃CN in 6 min,finally under these conditions for 0.5 min.] purity is >95%, Rt=2.606min; MS Calcd.: 285.1; MS Found: 286.1 ([M+1]⁺).

Example 5 Synthesis of Compound (271)

The Compound (271) was prepared according to the following steps:

a) Compound 45

To a stirred solution of compound 37 (2.5 g, 5.3 mmol) in DCM (20 mL)was added a solution of diazomethane in Et₂O (53 mmol). After stirringfor 12 h at room temperature, the mixture was concentrated in vacuo togive 45 (2.37 g, 92% yield), which was used without purification in nextstep.

b) Compound 46

A stirred solution of compound 45 (250 mg, 0.514 mmol) in HCl/EtOAc (10ml, 2.9 M) was stirred for 2 h at room temperature. The solvent wasremoved in vacuo to give crude 46 (147 mg, 100% yield), which was usedwithout purification in next step.

1H NMR (400 MHz, CDCl₃) □□ 1.26 (d, J=14.4 Hz, 6H), 1.95 (s, 3H),3.00-3.11 (m, 2H), 3.66 (s, 3H), 4.88-4.91 (m, 1H), 5.51-5.57 (m, 2H),5.71-5.75 (d, J=16.4 Hz, 1H), 7.02 (s, 1H), 7.13-7.23 (m, 2H), 7.37-7.39(d, J=8.4 Hz, 1H), 7.61-7.63 (d, J=7.6 Hz, 1H), 8.28 (s, 1H).

c) Compound 47

To a stirred solution of compound 46 (147 mg, 0.514 mmol) and Et₃N (79mg, 0.771 mmol) in THF (5 ml) was added Ac₂O (308 mg, 2.57 mmol) atice-water cooled under N₂ atmosphere. The mixture was warmed to roomtemperature and stirred for over night. The mixture was distilled withDCM (15 mL), washed with saturated NaHCO₃ aq (3 ml×2) and brine (5 ml).The combined organic layer was dried over Na₂SO₄ and concentrated togive the crude product which was purified by prepare Prep-TLC (DCM:MeOH=20:1) to afford the desired product 47 (150 mg, 89% yield).

d) Compound 271

To a stirred solution of compound 47 (150 mg, 0.457 mmol) in EtOH (4 ml)was added 4 N NaOH (1.4 mL). After stirring for 2 h at room temperature,the reaction mixture was adjusted to pH=5.0 with HCl (2 N) and dilutedwith DCM (40 mL), The organic phase was separated out, and the aqueouslayer was extracted with DCM/MeOH (10:1, 20 ml×2). The combined organiclayer was dried over Na₂SO₄ and concentrated to give the crude productwhich was purified by prepare TLC (DCM: MeOH=10:1) to afford the desiredproduct 271 (110 mg, 76% yield) as white solid.

¹H NMR (400 MHz, DMSO-d₆) □□ 1.09 (s, 3H), 1.14 (s, 3H), 1.80 (s, 3H),3.66 (s, 3H), 2.82-2.85 (m, 2H), 4.50-4.53 (m, 1H), 6.95-6.99 (m, 1H),7.04-7.07 (m, 2H), 7.32-7.34 (d, J=8 Hz, 1H), 7.53-7.55 (d, J=7.6 Hz,1H), 7.92-7.94 (d, J=8.4 Hz, 1H), 10.79 (s, 1H), 12.22 (s, 1H). LCMS(mobile phase: from 95% water (0.02% NH4Ac) and 10% CH₃CN to 40% water(0.02% NH4Ac) and 60% CH₃CN in 6 min, finally under these conditions for0.5 min.) purity is >95%, Rt=2.687 min, MS Calcd.: 314.1; MS Found:315.2 (M⁺+H).

Examples 6 to 14

The following indole derivatives (E6 to E14) and (E 14a to E 14j) can beprepared in analogy to the examples 1 to 5 by using appropriate startingmaterials.

B) Formulation Examples

The following examples are given by way of illustration for compositionsof compounds of formula (I). As active ingredient, the compoundaccording to example 1 can be used in the following compositions.

Example 15 Tablet Formulation

A formulation for a tablet containing 10 milligrams of the activeingredient of example 1 is as follows:

mg Active Ingredient 10 Lactose 61 Microcrystalline Cellulose 25 Talcum2 Magnesium stearate 1 Colloidal silicon dioxide 1

Example 16 Coated Tablet Formulation

Another suitable formulation for a tablet containing 100 mg of thecompound of example 2 is as follows:

mg Active Ingredient 100 Polyvinylpyrrolidone crosslinked 10 Potatostarch 20 Polyvinylpyrrolidone 19 Magnesium stearate 1 MicrocrystallineCellulose 50 Film coated and colored. The film coating material consistsof: Hypromellose 10 Microcryst. Cellulose 5 Talcum 5 Polyethylene glycol2 Color pigments 5

Example 17 Capsule Formulation

A suitable formulation for a capsule containing 50 milligrams of theactive ingredient of example 1 is as follows:

mg Active Ingredient 50 Corn starch 26 Dibasic calcium phosphate 50Talcum 2 Colloidal silicon dioxide 2

This formulation is filled in a gelatin capsule.

Example 18 Solution for Injection

A suitable formulation for an injectable solution is as follows:

Active Ingredient mg 10 Sodium chloride mg q.s. Water for Injection mLad 1.0

Example 19 Liquid Formulation

A suitable formulation for 1 liter of an ophthalmic solution containing2 milligrams of active ingredient in one milliliter of the mixture is asfollows:

mg Active Ingredient 2 Sorbitol 150 Buffering agent q.s. Colorant q.s.Purified water Ad 1000 ml

Example 20 Ophthalmic Formulation

100 g of the solution contain:

g Active Ingredient 0.1 Hydroxyethylcellulose 0.4 Sodium cloride q.s.Purified water ad 100 g

Example 21 Suspension Formulation

1.0 g of the suspension contains the following:

g Active Ingredient 0.10 Hypromellose 0.01 Purified water Ad 1.0 g

Hypromellose is dispersed in water homogeneously with a high speedmixer/blender. After about one hour of hydration time of thehypromellose, the active ingredient is blended homogeneously into thehypromellose solution. The viscosity of the suspension can be adjustedby the amount of hypromellose, resulting in a very stable suspensionwith a very slow tendency of particle sedimentation and particleagglomeration.

Example 22 Solution for Injection

1.0 ml of solution contain:

g Active Ingredient 0.05 Mannitol q.s. DMSO 0.10 Water for injection Ad1.0 ml

The active ingredient is dissolved in DMSO by stirring and heating(solution 1). The mannitol is dissolved in WFI (solution 2). Aftercooling down to room temperature solution 1 is mixed with solution 2 bycontinuous stirring. The solution is sterilized by filtration of byautoclaving.

C) Pharmacology Tests

The compounds of formula (I) of the present invention and pharmaceuticalcompositions containing them are characterized by advantageousproperties. The compounds and pharmaceutical compositions exhibit, instandard accepted reliable test procedures, the following valuableproperties and characteristics:

Pharmacological Testing Model 1

In an experimental model of glaucoma, there is increased expression ofamyloid precursor protein (APP) and likely related apoptosis in retinalganglion cells (RGC) [McKinnon, S. J., “Caspase activation and amyloidprecursor protein cleavage in rat ocular hypertension”, InvestOphthalmol Vis Sci. 2002 April; 43(4):1077-87]. Furthermore, injectionof Aβ₁₋₄₂ induces apoptosis in RGC. Interference with APP-Aβ pathwaysuch as inravitreal application of antibody, inhibition of β-secretaseactivity or oligomerisation inhibition prevents, at least temporally(depending on the treatment) RGC apoptosis in glaucoma resulting fromincreased ocular pressure (Guo, et al., 2007). Therefore, it can beconcluded that substances of formula (I), which exhibit a dual mechanismof action, i.E., β-sheet breaking activity and oligomerisationinhibition, show a neuroprotective activity.

In the male Dark Agouti rat model, glaucoma is produced by injection of50 μl of hypertonic saline into episcleral vein of one eye to induceincreased ocular pressure (chronic ocular hypertension—OHT), while theopposite eye serves as a control [Morrison J. C., “A rat model ofchronic pressure-induced optic nerve damage”, Exp Eye Res. 1997; 64(1):85-96]. In treatment groups (N=4-6 per group), various doses ofsubstances of the present invention are injected intravitreally (in 5 μlvolume) shortly before the glaucoma induction. The extent of RGCapoptosis at 3 weeks and 6 weeks after chronic ocular hypertension (OHT)induction is assessed in each animal by dynamic confocal scanning laserophthalmoscopy and fluorescent-labeled Annexin V.

Animals are sacrificed after 6 weeks and their eyes are enucleated andfixed in 4% paraformaldehyde overnight. Afterwards, retinas areseparated for assessing apoptosis related changes, for example: asvisualized with FITC Annexin V kit (BD Biosciences, Franklin Lakes, USA)[Cordeiro, M. F. 2004 “Real-time imaging of single nerve cell apoptosisin retinal neurodegeneration”, Proc Natl Acad Sci USA, 101, 13352-6;Kietselaer, B. L., 2003, “The role of labeled Annexin AS in imaging ofprogrammed cell death. Form animal to clinical imaging”, Q J Nucl Med,47, 349-61], or TUNEL (dUTP nick end labeling) [Roche, In situ celldeath detection kit, fluorescein labeled] [Szydlowsky K., Kaminska B.,2007, “Neuroprotective activity of selective mGlu1 and mGlu5 antagonistsin vitro and in vivo”, Eur. J. Pharmacol. 554, 18-29]. In animalstreated with experimental substances of the instant invention, there isa decrease in RGC apoptosis at the dose of 0.1 mg/ml least at one timepoint assessed.

Pharmacological Testing Model 2

In further experiments, rats are treated systemically (s.c.) and theexperiments are repeated as above. The aim of this study is to verifywhether systemic administration of a compound of formula (I) producingeye concentrations similar to those after intravitreal application alsoprovides neuroprotective effect against IOP-induced apoptosis. Inanimals treated systemically with the substances, there is a dosedependent decrease in RGC apoptosis reaching significance at the dose of240 mg/kg (mesylate) and observed at 6 weeks post glaucoma induction.

Pharmacological Testing Model 3

Additionally, effects of the compounds of formula (I) to monomericAβ₁₋₄₂ can be determined by surface plasmon resonance (SPR).

Materials and Methods

Preparation of Aβ

Aβ₁₋₄₂ (#60-0-80, American Peptide, Sunnyvale, Calif. USA) was dissolvedto 1 mg/ml in Hexafluoroisopropanol (HFIP). The tube was tightly sealedand incubated at room temperature for 1.5 h while shaking. 100 μgaliquots were prepared in low binding eppendorf tubes and frozen at −80°C. for 30-60 minutes. After lyophilization over night the aliquots werestored at −20° C. until use. One HFIP treated Aβ aliquot was thawed andfreshly dissolved in DMSO (anhydrous) and this 5 mM stock solution wasdiluted to 100 μM in 10 mM sodium acetate (pH4.0) immediately beforeimmobilization.

Surface Plasmon Resonance (SPR)

SPR studies were performed using a Biacore X100 biosensor instrument (GELifesciences, Uppsala, Sweden), equipped with two flow cells on a sensorchip. Aβ monomers were covalently coupled to one flow cell of CM7 sensorchips (GE Lifesciences, Uppsala, Sweden) via primary amines using theAmine Coupling Kit (GE Lifesciences, Uppsala, Sweden). As a control,ethanolamine was immobilized on the reference channel. 3 different chipswere used and immobilization levels for Aβ were comparable (21605RU,22180RU and 21929RU, respectively). One RU represents about 1 pg/mm² ofthe analytes on the surface matrix of the sensor chip.

Compounds were dissolved in DMSO and diluted further in DMSO to give1000× concentrated stock solutions. Then they were diluted 1:1000 inHBS-EP buffer which contains 0.01M HEPES, pH7.4, 0.15M NaCl, 3 mM EDTA,and 0.005% of surfactant P20. HBS-EP containing 0.1% (v/v) DMSO was usedas assay running buffer. Compounds were injected over the sensor chip inconcentrations ranging from 0.1 nM to 300 nM at a flow rate of 10μl/minfor 180 s at 25° C. Concentrations were tested in duplicate.

The RUs elicited by the compound injected into the ethanolamine controlflow cell was set as reference response and subtracted from the RUselicited by the same compound injected to the Aβ saturated flow cell.The relationships between each RU obtained at the steady state ofbinding (plateau of the binding curve) and each concentration of thecompound were plotted.

After the analyte injection was stopped, HBS-EP buffer was flowed overthe chip for 180 s to allow the bound analyte to dissociate from theimmobilized Aβ and the dissociation curves were obtained. After thedissociation phase, regeneration solution (1M NaCl, 50 mM NaOH) wasinjected and flowed over the chip for 30 s to remove the residual boundanalytes from the immobilized Aβ.

Biacore X100 control software Ver 1.1 was used to record the bindingcurves and Biacore X100 evaluation software Ver 1.1 to analyze them(plot each RU at the steady state vs. concentration of analyte, fit theplot, determine K_(D) values). The dissociation equilibrium constantK_(D) of the analyte to the immobilized Aβ was determined from thesteady-state levels estimating the maximum RU R_(max) and calculatingthe K_(D) as the concentration of the compound that elicited one-half ofthe R_(max).

By performing repeating tests, the following IC-50 values can be foundfor the example compounds:

Compound IC-50 (nM) Example 1 2.8 +/− 1.5 Example 2 1.4 +/− 1.0 Example3 0.5 +/− 0.3 Example 4 6.8 +/− 3.2 Example 5 42.1 +/− 0.7 

These data show that the compounds of formula (I) of the instantinvention are useful for the treatment of Alzheimer's Disease and forthe treatment of ocular diseases, such as glaucoma.

Moreover, plausible synergistic therapeutic effects can be found from acombined treatment with compounds of formula (I) and either intraocularpressure lowering agents currently used in glaucoma or other drugcompounds such as antioxidants, calcium channel blockers, NO synthaseinhibitors, neurotrophins and antiapoptotic agents.

Further synergistic effects can be found from a combined administrationof a compound of formula (I) (such as Example 1) and the drug compoundmemantine.

What is claimed is:
 1. A method for treating glaucoma comprising thestep of administering to a patient in need thereof a therapeuticallyeffective amount of a compound of formula (I)

wherein: R¹ is hydrogen, —C₁₋₆-alkyl, cycloC₃₋₁₂-alkyl, —C(O)—R or—C(O)OR; R² is hydrogen, —C₁₋₆-alkyl or cycloC₃₋₁₂-alkyl; R³ is —OR,—NHR or —NR₂; R⁴ is hydrogen, halogen, cyano, trifluoromethyl,—C₁₋₆-alkyl, —C₆₋₁₀-aryl, heteroaryl, —OR, —NHR, —NRR, —C(O)—R or—C(O)—NHR; R⁵ is hydrogen, —C₁₋₆-alkyl or C₂₋₆-alkenyl; R⁶ is hydrogen,—C₁₋₆-alkyl or C₂₋₆-alkenyl; or R⁵ and R⁶ together with the carbon atomscarrying them form a cyclic system with 3 to 6 carbon atoms; R ishydrogen, —C₁₋₆-alkyl, or —C₆₋₁₀-aryl; X is —C(O)CH₂—, —CH(OH)CH₂—,—CH═CH— or —CH₂—NH—C(O)—; and R⁷ is hydrogen, methyl, ethyl, propyl orcyclopropyl; or an optical isomer or a pharmaceutically acceptable saltthereof.
 2. The method of claim 1, wherein: R¹ is hydrogen, —C₁₋₆-alkyl,—C(O)—R or —C(O)OR; R² is hydrogen, —C₁₋₆-alkyl or cycloC₃₋₁₂-alkyl; R³is —OR, —NHR or —NR₂; R⁴ is hydrogen, halogen, cyano, trifluoromethyl,or —C₁₋₆-alkyl; R⁵ is —C₁₋₆-alkyl; R⁶ is —C₁₋₆-alkyl; or R⁵ and R⁶together with the carbon atoms carrying them form a cyclic system with 3to 6 carbon atoms; R is hydrogen, —C₁₋₆-alkyl, or —C₆₋₁₀-aryl; X is—C(O)CH₂—, —CH(OH)CH₂—, —CH═CH— or —CH₂—NH—C(O)—; and R⁷ is hydrogen,methyl, ethyl, propyl or cyclopropyl.
 3. The method of claim 1, wherein:R¹ is hydrogen, —C₁₋₆-alkyl, —C(O)—R or —C(O)—OR; R² is hydrogen or—C₁₋₆-alkyl; R³ is —OR, —NHR or —NR₂; R⁴ is hydrogen, halogen, cyano,trifluoromethyl, or —C₁₋₆-alkyl; R⁵ is hydrogen or —C₁₋₆-alkyl; R⁶ ishydrogen or —C₁₋₆-alkyl; or R⁵ and R⁶ together with the carbon atomcarrying them form a cyclic system with 3 to 6 carbon atoms R ishydrogen or —C₁₋₆-alkyl; X is —C(O)CH₂—, —CH(OH)CH₂—, —CH═CH— or—CH₂NHC(O)—; and R⁷ is hydrogen or methyl.
 4. The method of claim 1,wherein: R¹ is hydrogen, —C₁₋₃-alkyl, or —C(O)—CH₃; R² is hydrogen or—C₁₋₃-alkyl; R³ is —OR, —NHR or —NR₂; R⁴ is hydrogen or halogen; R⁵ is—C₁₋₃-alkyl; R⁶ is —C₁₋₃-alkyl; R is hydrogen or —C₁₋₃-alkyl; X is—C(O)CH₂—, —CH(OH)CH₂—, —CH═CH— or —CH₂NHC(O)—; and R⁷ is hydrogen. 5.The method of claim 1, wherein: R¹ is hydrogen, —C₁₋₃-alkyl, or—C(O)—CH₃; R² is hydrogen; R³ is —OR —NHR; R⁴ is hydrogen; R⁵ ishydrogen or —C₁₋₃-alkyl; R⁶ is hydrogen or —C₁₋₃-alkyl; R is hydrogen or—C₁₋₃-alkyl; X is —C(O)CH₂—, —CH(OH)CH₂—, —CH═CH— or —CH₂NHC(O)—; and R⁷is hydrogen.
 6. The method of claim 1, wherein: R¹ is hydrogen or—C(O)—CH₃; R² is hydrogen; R³ is —OR —NHR; R⁴ is hydrogen; R⁵ is—C₁₋₃-alkyl; R⁶ is —C₁₋₃-alkyl; R is hydrogen or —C₁₋₃-alkyl; X is—C(O)CH₂—, —CH(OH)CH₂—, —CH═CH— or —CH₂NHC(O)—; and R⁷ is hydrogen. 7.The method of claim 1, wherein the group X is —C(O)CH₂— or —CH(OH)CH₂—or —CH═CH—.
 8. The method of claim 1, wherein the chiral center carryingthe amino group and the group X has R-configuration.
 9. The method ofclaim 1, wherein said compound is selected from the group consisting of:N—((R)-2-amino-3-(1H-indol-3-yl)-propyl)-2,2-dimethyl-malonamic acid,(E)-(R)-5-amino-6-(1H-indol-3-yl)-2,2-dimethyl-hex-3-enoic-acid,(E)-(R)-5-amino-6-(1H-indol-3-yl)-2,2-dimethyl-hex-3-enoic acid amide,(E)-(R)-5-amino-6-(1H-indol-3-yl)-2,2-dimethyl-hex-3-enoic-acid-methylamide,(E)-(R)-5-acetylamino-6-(1H-indol-3-yl)-2,2-dimethyl-hex-3-enoic-acid,(R)-5-amino-6-(1H-indol-3-yl)-2,2-dimethyl-4-oxo-hexanoic-acid,(R)-5-amino-4-hydroxy-6-(1H-indol-3-yl)-2,2-dimethyl-hexanoic-acid,(R,E)-6-(1H-indol-3-yl)-2,2-dimethyl-5-(N-methylacetamide)hex-3-enoicacid,(E)-(R)-5-acetylamino-6-(1H-indol-3-yl)-2,2-dimethyl-hex-3-enoic-acid-amide,(E)-(R)-5-acetylamino-6-(1H-indol-3-yl)-2,2-dimethyl-hex-3-enoic-acid-methylamide,(E)-(S)-5-amino-6-(1H-indol-3-yl)-2,2-dimethyl-hex-3-enoic-acid-amide,(E)-(S)-5-amino-6-(1H-indol-3-yl)-2,2-dimethyl-hex-3-enoic-acid-methylamide,(R)-5-amino-6-(1H-indol-3-yl)-2,2-dimethyl-4-oxo-hexanoic-acid-methylamide,(R)-5-acetylamino-6-(1H-indol-3-yl)-2,2-dimethyl-4-oxo-hexanoic acid,(R)-N1-(2-amino-3-(1H-indol-3-yl)propyl)-2,2-dimethylmalonamide,(R,E)-3-(3-amino-4-(1H-indol-3-yl)but-1-en-1-yl)oxetane-3-carboxylicacid,(R,E)-3-(3-amino-4-(1H-indol-3-yl)but-1-en-1-yl)oxetane-3-carboxyamide,(R)-3-((2-amino-3-(1H-indol-3-yl)propyl)carbamoyl)oxetane-3-carboxylicacid, (R)-N-(2-amino-3-(1H-indol-3-yl)propyl)oxetane-3,3-dicarboxamide,(R)-3-((2-(3,3-dimethylbutanamido)-3-(1H-indol-3-yl)propyl)amino-2,2-dimethyl-3-oxopropanoicacid,(R)-N1-(2-(3,3-dimethylbutanamido)-3-(1H-indol-3-yl)propyl)-2,2-dimethylmalonamide,(R)-3-((3-(1H-indol-3-yl)-2-pivalamidopropyl)amino)-2,2-dimethyl-3-oxopropanoicacid,(R)-N1-(3-(1H-indol-3-yl)-2-pivalamidopropyl)-2,2-dimethylmalonamide,(R)-N1-(2-amino-3-(1H-indol-3-yl)propyl)-N3-(tert-butyl)-2,2-dimethylmalonamide,and pharmaceutically acceptable salts thereof.